Surface-modified acid crystals and process for their preparation

ABSTRACT

The invention relates to acid crystals the surface of which consists at least partially of a dehydrated water soluble salt. The preparation thereof is characterized in that the acid crystals are mixed with a metal oxide or hydroxide and the obtained mixture is reacted under substantially anhydrous conditions in the presence of traces of water. These modified crystals are very suitable to use as the acidic component in various mixtures, e.g. in effervescent mixtures, as these crystals can absorb some moisture without starting the carbon dioxide development. Tablets containing the acid crystals of the invention are hard when freshly prepared and show the tendency to gain in hardness on exposure to the atmosphere for some days. Moreover they are completely water-soluble with a delayed acid release.

United States Patent [4 1 May 16, 1972 Gergely [54] SURFACE-MODIFIEDACID CRYSTALS AND PROCESS FOR THEIR PREPARATION [72] Inventor: GerhardGerfely, Vienna, Austria [73] Assignee: Organon Inc., West-Orange, NJ.

[22] Filed: Mar. 26, 1970 [21] Appl. No.: 23,005

[30] Foreign Application Priority Data Mar. 26, 1969 Germany ..P l9 15509.0

[52] U.S.Cl. ..117/100A, ll7/ll8,260/535P [51] Int. Cl ..C07c 55/02 [58]FieldofSear-ch ..117/100BA,118;252/39l; 260/535 P [56] References CitedUNITED STATES PATENTS 3,476,588 ll/l969 Pitel ..l l7/10O 3,518,3436/1930 Welsh..... .117/100 X 3,354,863 11/1967 Reynolds ....1 17/100 X1,936,364 11/1933 Pasternack et al ....260/535 X 3,001,228 9/1961 Nack..117/100X 3,206,477 9/1965 Haga ..260/535 3,420,881 l/l969 Turco et al...260/535 3,131,068 4/1964 Greif et al ..260/535 X FOREIGN PATENTS ORAPPLICATIONS 449,675 7/1948 Canada ..260/535 Primary Examiner-William D.Martin Assistant Examiner-Mathew R. P. Perrone, Jr. AttorneyHugo E.Weisberger [5 7] ABSTRACT The invention relates to acid crystals thesurface of which consists at least partially of a dehydrated watersoluble salt. The preparation thereof is characterized in that the acidcrystals are mixed with a metal oxide or hydroxide and the obtainedmixture is reacted under substantially anhydrous conditions in thepresence of traces of water. These modified crystals are very suitableto use as the acidic component in various mixtures, e.g. in effervescentmixtures, as these crystals can absorb some moisture without startingthe carbon dioxide development. Tablets containing the acid crystals ofthe invention are hard when freshly prepared and show the tendency togain in hardness on exposure to the atmosphere for some days. Moreoverthey are completely water-soluble with a delayed acid release.

11 Claims, No Drawings SURFACE-MODIFIED ACID CRYSTALS AND PROCESS FORTHEIR PREPARATION This invention relates to novel modified acids andtheir preparation, as well as to tablets comprising these modifiedacids.

BACKGROUND OF THE INVENTION In the preparation of tablets which are todisintegrate in water the problem often occurs that the tablets obtainedare brittle and disintegrate during prolonged storage when exposed tothe air. Further the problem may arise that the tablets are hard anddisintegrate only after a prolonged period of time if at all.

With tablets which comprise both acidic and basic components the problemoften occurs that acids and bases are incompatible since they will forma precipitate in aqueous solutions. This occurs, for example, on usingcitric acid and a water-soluble calcium salt. On application of saidcombination a water-insoluble calcium citrate will be formed. Theformation of a precipitate is not only objectionable from an estheticviewpoint, but it will also cause difficulties in the administration ofmeasured amounts of anions and cations. Moreover, the formation of aprecipitate will have an adverse effect on the effervescence ofeffervescent tablets. Moreover, with the known tablets containing anacid and a carbonate or bicarbonate the development of carbon dioxidestarts soon after absorption of some moisture from the surrounding air,so that the tablets will disintegrate prematurely.

SUMMARY OF THE INVENTION It has now been found that the abovedisadvantages can be overcome largely or completely by means of thenovel modified acids. These modified acids are characterized in thatthey consist of crystals the surface of which is formed partially orcompletely by a dehydrated water-soluble salt.ln the preparation ofthese modified acids attention has to be paid only that the cations assuch should not form a water-insoluble salt with the acid directly. Acidand salt have the same anion. It is, however, also possible to usemixtures of each of the components. This will be discussed in moredetail below.

The modified acids according to the invention can be prepared by mixingcrystals of an acid with a metal oxide or hydroxide, hereinafter alsoindicated as the metal compounds, under substantially anhydrousconditions in the presence of a small amount of a substantiallyanhydrous organic solvent. The copresence of a trace of water, usuallyless than 1 percent based on the total weight of the mixture, isessential to initiate the reaction. The surface of the acid crystals isthus wetted. It is assumed that the surface of the acid is dissolved, atleast partially, whereupon it reacts while dissolved with the metalcompound, whereupon the formed salt, probably a basic salt, willprecipitate on the surface of the crystals. After some time the crystalsurfaces show shallow spots or cavities. It is therefore assumed thatthe reaction is not limited to the initial surface but penetrates intothe crystal at least partially.

Another method to modify the acid crystals consists of mixing the acidcrystals with dry crystals of the metal compound in a fluidized bedwhich is maintained by means of an inert gas which contains a smallamount of substantially dry solvent for the acid.

Yet another method consists of spray-drying a solution or a dispersionof the metal compound onto the acid crystals under substantiallyanhydrous conditions.

It is also possible to mix the acid crystals and the metal compound andto bring the mixture into an atmosphere which is saturated with thevapor of a solvent for the acid.

Many possible variations of the above methods will be obvious to theexpert in the field of topochemistry. An example of a variation of thattype is the method in which a fluidized bed is made of acid crystalsonly by means of the inert carrier gas,

such as for example air, the carrier gas containing ammonia togetherwith traces of water.

The modified acid crystals preferably contain both crystalline salt andany residual acid crystal in anhydrous form though partially dehydratedmodified acid crystals are also useful.

Suitable acids to be used as starting material in the process of thepresent invention are those acids which are crystalline underatmospheric conditions in combination with metal compounds of which thecation forms a water-soluble salt with the acid anion. This can beeither a normal water-soluble salt, usually a basic salt, or awater-soluble complex salt. Suitable acids are organic acids andparticularly polybasic organic acids, for example adipic acid, fumaricacid, malic acid, maleic acid, malonic acid, succinic acid, sebacicacid, acetosalicylic acid, citric acid, ascorbic acid, gluconic acid,sugar acids, ethylene diamine tetraacetic acid (hereinafter abbreviatedto EDTA), cinnamic acid, cyclamic acid and 'yand 8-lactones which reactunder the prevailing reaction conditions as the corresponding 7- and8-hydroxy carboxylic acids.

Suitable metal compounds are the oxides and hydroxides of alkali metaland alkaline earth metal as well as of magnesium, aluminum, tin, ferro,nickel, cobalt, silver and lead. The term alkali metal in thisspecification also comprises ammonia and strong basic amines. Somemetals are preferably added as oxide, such as, for example, magnesium.Other metals are preferably added as hydroxides, such as, for example,tin, nickel, aluminum, the alkaline earth metals and the metals of theiron group of the periodic system.

Even though the final product preferably comprises only one anion, itmay yet comprise two or more different anions simultaneously, providedthat no precipitate will be formed on dissolution in water. Thus, forexample, fumaric or citric acid and cyclamic acid can be crystallizedsimultaneously from a solution. Also cyclamic acid can be crystallizedfrom a solution onto fumaric or citric acid crystals prior to the startof the topochemical reaction according to the invention.

The modified acid crystals according to the invention are easily solublein water with a delayed acid release. They are very suitable to use asthe acidic component in various mixtures e.g. in effervescent mixtures,as they can absorb some moisture without starting the carbon dioxidedevelopment. Incorporated in tablets the modified acid does not react orif at all, very slowly with any metal compound present. The tablets arereadily soluble in water without forming a precipitate. No precipitatewill occur within an hour from the moment the tablet has completelydissolved. The tablets are also hard when freshly prepared and show thetendency to gain in hardness on exposure to the atmosphere for at leasttwo days. For storage of the tablets over a prolonged period of time ofmany months or years it is preferred to store them in an enclosed space,thus ensuring an equilibrium between the tablets and the surroundingatmosphere in said enclosed space.

If efi'ervescent tablets are to be prepared it is a simple matter ofincorporating a suitable agent capable of developing gas in an aqueousmedium. Usually this agent is either a carbonate or a bicarbonate. Fromthe above it will be evident that these additives in turn should, bypreference, be partially or completely dehydrated.

In this respect it should be observed that the tablets according to theinvention are harder and less brittle than corresponding tablets inwhich all components are fully hydrated. With respect to theeffervescent tablets of the invention it is to be observed that theseare superior to the commonly known effervescent tablets. The latter arebrittle and show a distinct tendency to fall apart to a powder.

Solvents suitable to be used in the preparation of the modified acidcrystals are for example chloroform, carbon tetrachloride, diethylether,diisopropylether, methylene chloride, isopropylalcohol, petroleumether,toluene and methanol. The solvents should be substantially anhydrous.

Suitable amounts of water required to induce the reaction can vary from0.01 percent 2 percent by weight of the total mixture of reactants butpreferably the amount of water is between 0.l percent and 0.5 percent byweight.

The following examples illustrate the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE I 5.5 Kg of powderedanhydrous citric acid and 925 g. of calcium-hydroxide were mixed for 2minutes in a. vacuum mixer of stainless steel. To this mixture was added2 l of dry 1 EXAMPLE II The procedure of Example I was repeated usingthe following ingredients: 7.3 kg of anhydrous adipic acid (120 mesh)and 3.6 kg of calciumhydroxide. 2.8 l of methylene chloride were used.The resulting powder dissolves readily in water and does not giveprecipitation of calcium adipate within 3 hours.

EXAMPLE Ill The following components were mixed after drying in a mixer(45 l) in the amounts indicated:

citric acid 8.19 kg adipic acid 0.18 kg calciumhydroxide l 68 kg untilthe granule size was between 0.05 and 0.l mm. A small sample of thismixture shows an acidic reaction on a moist pH paper. To the abovemixture were added 500 ml of dry methylene chloride with stirring, whichwas continued for minutes.

At the same time a methanolic solution had been prepared in a roundbottom vessel (2 1) provided with a reflux cooler, as follows: 150 g ofcitric acid and 80 g of cyclamic acid were dissolved in 150 ml methanolwith mild boiling of the solvent. The boiling was continued for 2minutes. Subsequent to the boiling 100 ml cold methanol were added. Themethanolic solution thus obtained was mixed with the methylene chloridebatch with stirring for seconds, after which the solvents wereevaporated. A dry powder of colored granules was obtained. The powderdissolves readily in water without forming any precipitate within 3hours.

EXAMPLE IV A mixture of 5.5 kg of citric acid, 600 g of ascorbic acidand 650 g of adipic acid (all powdered) was mixed for 2 minutes at lowspeed in a mixer as used in Example I. 2.8 kg of calciumhydroxide wereadded to the mixture thus obtained and the stirring was continued foranother 2 minutes, whereafter 4.2 l of chloroform were added. Afterstanding for minutes the solvent was removed by evaporation undervacuum. To the substantially dry product were then added 0.8 l of drymethanol and L9 kg of Na CO .K CO with stirring for 2 minutes.Thereafter the solvent was evaporated at 45 C until a fully dry productwas obtained. The resulting powder were pressed to tablets whichdissolve readily in water with effervescence without any precipitatebeing formed within 5 hours.

est in EXAMPLE V 30 Kg of citric acid crystals were introduced in acontainer provided withan inlet and an outlet for the circulation ofgas. he gas circuit is arranged in a manner that the gas can optionallybe circulated in a closed circuit. A small amount of methanol l l) wasintroduced in the container. The gas circulation (air) was started in aclosed circuit and substantially all methanol evaporated. Then 400 g ofdry ammonia gas was in- 0 troduced in the gas current whereafter the gascirculation was continued for 15 minutes. Subsequently 1 kg of sodiumcarbonate was added, which stopped further reaction. The gas current wasinterrupted and fresh dry air was blown through until the reactionmixture was fully dry. The resulting product was free flowing andpassive to water vapor, but it dissolved rapidly in water.

Tablets made with the product thus obtained are not brittle maintainingthese properties on storage for 3 months and dissolved readily in waterwith increasing effervescence, without forming a precipitate.

EXAMPLE VI In a vacuum mixer of stainless steel 4 kg of powderedanhydrous citric acid and 420 g of magnesium oxide were mixed for 3minutes. To this mixture was added 1.4 l of dry methylene chloride,whereafter the mixer was closed to prevent evaporation. After stirringthe mixture for an additional 20 minutes 350 ml of dry methanol wereadded and the mixing continued for 3 minutes, after which the methylenechloride was evaporated in vacuum. Finally the methanol and the rest ofthe methylene chloride were removed by evaporation in vacuum at 50 C.The powder obtained was free flowing and readily and completely solublein water without any precipitation of a magnesium salt.

What is claimed is:

1. Process for the preparation of acid crystals the surface of which isformed at least partially of a dehydrated water-soluble basic salt ofthe acid, comprising the steps of wetting a dry mixture of water-solubleorganic acid crystals and a compound of a metal the cation of whichforms a water-soluble salt with the anion of said acid, with asubstantially anhydrous organic solvent for said acid, in the presenceof an amount of water between about 0.01 percent and about 2 percent byweight of the total dry mixture, thereby forming said basic salt on thesurface of said acid crystals, and thereafter drying said mixture.

2. The process of claim 1 in which said metal compound is selected fromthe group consisting of calcium oxide, calcium hydroxide, magnesiumoxide, and magnesium hydroxide.

3. The process of claim 1 in which the acid is a polybasic organic acid.

4. The process of claim 1 in which the acid is citric acid.

5. The process of claim 1 in which the amount of water is between about0.1 percent and about 0.5 percent by weight of the dry mixture.

6. The process of claim 1 in which the solvent is methylene chloride.

7. Organic acid crystals, the surface of which is formed at leastpartially of a dehydrated water-soluble basic metal salt of the acid,said crystals being readily soluble in water with a delayed acidrelease.

8. The composition of claim 7 which is in the form of a tablet.

9. The composition of claim 7 in which the acid is citric acid.

10. The composition of claim 7 in which the metal is selected from thegroup consisting of calcium and magnesium.

11. The composition of claim 7 in which the metal is calciurn.

I UNITED STATES PATENT OFFICE CERTIFICATE @F CGRRECTION Patent No.3,663,271 L Dated May 16, 1972 Inventorbs) Gerhard Gergely It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Change the name of the inventor to: Gerhard Gergely.

Signed and sealed this 26th day of September 1972.

(SEAL) Attest:

EDWARD M. FLETCHER, JR. Attesting Officer ROBERT GOTTSCHALK Commissionerof Patents ORM po'wso USCOMM-DC 60376-P69 9 U.S. GOVERNMENT PRINTINGOFFICE: 1969 03G-334

2. The process of claim 1 in which said metal compound is selected fromthe group consisting of calcium oxide, calcium hydroxide, magnesiumoxide, and magnesium hydroxide.
 3. The process of claim 1 in which theacid is a polybasic orGanic acid.
 4. The process of claim 1 in which theacid is citric acid.
 5. The process of claim 1 in which the amount ofwater is between about 0.1 percent and about 0.5 percent by weight ofthe dry mixture.
 6. The process of claim 1 in which the solvent ismethylene chloride.
 7. Organic acid crystals, the surface of which isformed at least partially of a dehydrated water-soluble basic metal saltof the acid, said crystals being readily soluble in water with a delayedacid release.
 8. The composition of claim 7 which is in the form of atablet.
 9. The composition of claim 7 in which the acid is citric acid.10. The composition of claim 7 in which the metal is selected from thegroup consisting of calcium and magnesium.
 11. The composition of claim7 in which the metal is calcium.